Environmental Monitoring Handbook

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C O N T E N T S ENVIRONMENTAL MONITORING  — H A N D B O O K —  Environmental Monitoring Risk Assessment

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By Tim Sandle 

Section One: Determining The Frequency of Monitoring Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Assessmentt Tools Tools . . . . . . . . . . . . . 8 Section Two: Risk Assessmen

Section Three: Num Numeri erical cal Appro Approach aches es . . . . . . . . . . . 15 Crit itic ical ality ity Sco Scori ring ng . . . . . . . . . . . . . . . 24 Section Four: Cr

Section Five: Co Conc nclu lusio sion n . . . . . . . . . . . . . . . . . . . . . 26

Issues That can Affect The Accuracy of Environmental Monitoring Data 

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By Freancesco Boschi, Ph.D.

Section One: Issues Related to EM Sampling Technique  .

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Section Two: Issues Related to EM Sampling Instrumentation and Incubation Equipment 

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Section Five: Issues Related To Documentation Practices  .

Section Six: Conclusion

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Section Three: Issues Related to Culture Media  Section Four: Issues Related to Isolation  And Recovery of Microorganisms

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Environmental Monitoring

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Environmental Monitoring Risk Assessment  Tim Sandle  By Tim By 

INTRODUCTION Environmental Monitoring describes the microbiological testing undertaken in order to detect changing trends of microbial counts and microflora growth growth within cleanroom or controlled environments. The results obtained provide information about the physical construction of the room, the performance of the Heating, Ventilation, and Air-Conditioning (HVAC) system, personnel cleanliness, gowning practices, the equipment, and cleaning operations. Over the past decade, environmental monitoring has become more sophisticated in moving from random sampling, using an imaginary grid over the room and testing in each grid, to the current focus on risk assessment and the use of risk assessment tools to determine the most appropriate methods for environmental monitoring. This paper explores current trends in the application of risk assessment to the practice of environmental monitoring by examining the following key areas: •

Determining the Frequency of Monitoring: Using the concept of risk assessment to decide how often to monitor different types of cleanrooms Risk Assessment Tools: Applying risk assessment tools to establish methods for environmental monitoring Numerical Approac Approaches: hes: Considering a numerical approach to assess risk data using a case study of an aseptic filling operation

• •

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The examples used are from a sterile drug manufacturing facility and focus mostly mostly on aseptic filling; howe however ver,, the concepts and tools are applicable to the environmental monitoring of other types of manufacturing and packaging operations.

DETERMINING THE FREQUENCY OF MONITORING In developing an adequate environmental monitoring programme, there should be a balance between using resources efficiently and monitoring at sufficiently frequent intervals so that a meaningful picture can be obtained. Sources of guidance with respect to monitoring frequencies are very limited within Europe, and the monitoring frequencies specified within the United States Pharmacopoeia (USP) may not be suitable for all facilities.. Some guidance can be obtained from the International facilities Organization for for Standardization’s Standardization’s (ISO) standards: standards: principally ISO 14644 and ISO 14698. Howe However ver,, these do not always fit with with regulatory guidance documents because they apply to controlled environments across a range of industries other than pharmaceuticals, where standards can be higher (Jahnke, 2001). When establishing an environmental control programme, the frequency of monitoring different controlled areas can be determined based on ‘criticality factors’ factors’ relev relevant ant to each specific area. Criticality Factors  The establishment of a criticality scheme on which to base monitoring frequencies is designed to target monitoring of critical process steps. Therefore, the final formulation process would receive more monitoring than an early manufacturing stage with a relatively closed process. Using a criticality factor is a means of assigning a monitoring frequency based on the risk assessment of each critical critical area. The risk assessment assessment relates to the potential product impact from any risk. For example, an area of open processing at an ambient temperature, a long exposure time, and the presence of water, would constitute a high risk and would attract a higher risk rating. rating. In contrast, contrast, an area of closed processing, processing, in a cold area, would carry a substantially lower risk and associated risk rating. Using a range range of 1 to 6, with ‘1’ being the most most critical critical and ‘6’ the least critical, a score of 1 would be assigned to an aseptic filling operation; operation; a score of 2 to final formulation, a score of 3 to open processing, and so on. Each user must adapt such a scheme to his or her particular area and defend it by way way of supportable rationale. An example of monitoring fre-

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quencies under such a scheme can be seen in Figure 1, and an example of its application is seen in Figure 2 .

Figure 1 Criticality Factors of Monitoring Frequencies Criticality Factor 1

Frequency of Monitoring Daily or Each Batch

Weekly 2  Each controlled area would be evaluatFortnightly or Bi-weekly 3 ed against set criteria Monthly 4  and, with the use of a Three-monthly or Quarterly 5 series of guiding quesSix-monthly or Semi-annually 6 tions, the monitoring frequency would be determined. Decision criteria include considerations in two category areas: areas of higher weighting and areas of higher monitoring frequency. Examples of these categories follow: ➤

Giving Higher Weighting to – ✓ ✓

✓ ✓ ✓ ✓

➤

‘Dirtier’ activity performed in a room adjacent to a clean activity, even if the clean activity represents later processing Areas that have a higher level of personnel transit (given that people are the main microbiological contamination source). This may include corridors and changing rooms. Routes of transfer Areas that receive in-coming goods Component preparation activities and sites Duration of activity (such as a lower criticality for a 30-minute process compared to a six-hour operation)

Having Higher Monitoring Frequencies for –

Warm or ambient areas as opposed to cold rooms ✓ Areas with water or sinks as opposed to dry, ambient areas ✓ Open processing or open plant assembly compared to processing that is open momentarily or to closed processing (where product risk exposure time is examined) ✓ Final formulation, purification, secondary packaging, product filling, etc. Once the monitoring frequency for each controlled area is determined, it should be reviewed at regular intervals. This review may invoke changes to a ✓

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room’s status, and hence, its monitoring frequency, or to changes for different sample types within the room. For example, it may be that after reviewing data for one year, surface samples produce higher results than air samples for a series of rooms. In this event, the microbiologist may opt to vary the frequency of monitoring and take surface samples more often than air samples. There would also be an increased focus on cleaning and disinfection practices, and their frequencies, based on such data (Sandle, 2004b). When both types of monitoring are producing low level counts, the balFigure 2  Application of Criticality Factors

Environmental Criticality Factor

Likelihood of Environmental Impact on Finished Product

1

Highly Likely

2

Likely

 Area of final formulation. This may apply to an area where the final process is a sterilizing grade filter.

Weekly

3

Moderately Likely

Direct or indirect exposure of the product to the environment is somewhat likely to introduce contaminants.

Fortnightly or Bi-Weekly

 

Definition

 Aseptic filling where no further processing takes place. Here the risk of contamination would have a considerable product impact because contaminants could not be reduced or removed by further processing.

Monitoring Frequency Daily or Each Batch

This may also apply to an area that is at ambient temperature and where there is a high water presence.

4

Unlikely

This may apply to cold areas where little or no open processing takes place.

5

 Very Unlikely

Indirect exposure to the environment is highly unlikely to introduce contaminates that could affect the finished product. If a contaminant were to be introduced, sufficient downstream controls and/or the use of preservative agents are highly likely to remove and significantly reduce contaminants.

6

High Unlikely

 An area that is uncontrolled or where microbial contamination is very unlikely, such as a freezer.

Monthly

Every 3 Months or Quarterly

Environmental Monitoring

Every 6 Months or Semi-annually

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ance of risk would be toward air samples. This is because air samples are direct indicators of the quality of the process and assign a level of control to the process, whereas surface samples are indicators of cleaning and disinfection. If the results of surface samples are generally satisfactory, as indicated by trend analysis, then either the number of samples or the frequency at which they are taken can be reduced. If subsequent data showed an increase in counts, the monitoring frequency could easily be restored. Indeed, all types of monitoring frequencies may increase as part of an investigation, as appropriate. Therefore, the criticality factor approach not only sets the requirement for a room, it can also be used to vary the sample types within a room (Ljungqvist and Reinmuller, 1996).

RISK ASSESSMENT TOOLS Once the status for each room has been selected, a risk assessment procedure is required to determine locations for environmental monitoring. Such risk-based approaches are recommended in ISO 14698 and regulatory authorities are increasingly asking drug manufacturers about this subject. Risk-based approaches include Failure Mode and Effects Analysis (FMEA), Fault Tree Analysis (FTA), and Hazard Analysis and Critical Control Points (HACCP), all of which employ a scoring approach. (Other approaches include: Failure Mode, Effects, and Criticality Analysis (FMECA); Hazard Operability Analysis (HAZOP); Quantitative Microbiological Risk Assessment (QMRA); Modular Process Risk Model (MPRM); System Risk Analysis (SRA); Method for Limitation of Risks; and Risk Profiling.) At present, no definitive method exists, and the various approaches differ in their process and in the degree of complexity involved. However, the two most commonly used methods appear to be HACCP, which originated in the food industry, and FMEA, which was developed for the engineering industry (Whyte and Eaton, 2004a). These various analytical tools are similar in that they involve: • • • • • •

Constructing diagrams of work flows Pin-pointing areas of greatest risk Examining potential sources of contamination Deciding on the most appropriate sample methods Helping to establish alert and action levels Taking into account changes to the work process and seasonal activities

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These risk assessment approaches are not only concerned with selecting environmental monitoring locations. They integrate the environmental monitoring system with a complete review of operations within the cleanroom to ensure those facilities, operations, and practices are also satisfactory. The approaches recognise a risk, rate the level of the risk, and then set out a plan to minimise, control, and monitor the risk. The monitoring of the risk will help to determine the frequency, locations for, and level of environmental monitoring (for example, refer to an article by Sandle [2003a], for a more detailed example). This paper explores an example from three different techniques: • • •

A simple conceptualisation of risk using a table HACCP FMEA

Tabular Approach  An example using a simple table for analyzing risk in environmental monitoring situations appears in Figure 3 .

Figure 3  Tabular Approach to Risk Assessment Area or Equipment: Sterility Testing Isolator Risk: Contamination due to build-up of microbial counts in the isolator environment Failure or Situation: Failure to adequately clean after use

 

Effect

• When isolators are not cleaned regularly, there is a possibility of micro-organisms remaining in the environment.

Minimising the Risk (Mitigations to Reduce Risk) • Cleaning surfaces using water to remove dirt or spillages prior to the application of a suitable disinfectant. • The disinfectant used must have a wide spectrum of efficacy, but not be aggressive to the isolator material. • The isolator should be designed so that it is easy to clean.

 

Monitoring

• An environmental monitoring programme (using settle plates, air samples, contact plates, swabs, or finger plates) will show the areas of greatest risk. This data should be examined for trends. • For out-of-limits environmental monitoring results, appropriate Corrective and Preventive Actions (CAPA) should be put in place.

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HACCP ➤

The seven principles behind constructing an HACCP analysis consist of: 1. Identifying hazards or contamination risks and assessing their severity 2. Determining Critical Control Points (CCPs) 3. Establishing critical limits 4. Establishing a system to monitor and control CCPs 5. Establishing corrective action when a CCP is not under control 6. Establishing procedures for verification to confirm that the HACCP system is working effectively 7. Establishing documentation and reporting systems for all procedures

Each of these seven key points is a vital step in developing the risk assessment. ➤

The seven points include:  1. Construct a risk diagram, or diagrams, to identify sources of contamination. Diagrams should show sources and routes of contamination. Examples include: ✓ Areas adjacent to Cleanroom or Isolator (e.g.: airlocks, changing rooms) ✓ Air supply and Room air ✓ Surfaces ✓ People ✓ Machines and Equipment 2. Assess the importance of these sources and determine whether or not they are hazards that should be controlled. Examples include: ✓ Amounts of contamination on, or in, the source that is available for transfer ✓ Ease by which the contamination is dispersed or transferred ✓ Proximity of the source to the critical point where the product is exposed ✓ Ease with which the contamination can pass through the control method

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The use of a scoring method can greatly help in assessing the relative importance of these contamination sources. 3. Identify the methods that can be used to control these hazards. For example: ✓ Air Supply: High Efficiency Particulate Air (HEPA) filters ✓ Dirty Areas adjacent to Cleanroom or Isolator: differential pressures, airflow movement ✓ Room Air: air change rates, use of barriers ✓ Surfaces: sterilisation, effectiveness of cleaning and disinfection procedures ✓ People: cleanroom clothing and gloves, room ventilation, training ✓ Machines and Equipment: sterilisation, effectiveness of cleaning, exhaust systems 4. Determine valid sampling methods to monitor either the hazards or their control methods or both. For example: ✓ HEPA filter integrity tests ✓ Air supply velocity, air change rates ✓ Room pressure differentials ✓ Particle counts ✓ Air samplers, settle plates, contact plates, etc. 5. Establish a monitoring schedule with ‘alert’ and ‘action’ levels and the corrective measures to be taken when these levels are exceeded. For example: ✓ The greater the hazard, the greater the amount of monitoring required ✓ Trend analysis for alert and action levels, in or out of control

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6. Verify that the contamination control system is working effectively by reviewing key targets like product rejection rate, sampling results, control methods, and so on. These may require modification over time. For example: ✓ System for data review ✓ Examine filling trials ✓ Audits ✓ Reassess - hazards, effectiveness of control systems, frequency of monitoring, appropriateness of alert and action levels 7. Establish and maintain documentation. For example: ✓ Describe the steps being taken ✓ Describe the monitoring procedures ✓ Describe the reporting and review procedures Before implementing HACCP, it is important to train all staff involved in the process and to use a multi-disciplinary team. For example, the team may be comprised of personnel from Production, Engineering, Quality Control (QC), Quality Assurance (QA), Validation, and so on. FMEA FMEA schemes vary in their approach, scoring, and categorisation. All methods share a numerical approach. The example presented here, based on a sterility testing isolator, assigns a score (from 1 to 5) to each of the following categories: Severity ➤ Occurrence ➤ Detection ➤

Where: ✓ Severity is the consequence of a failure ✓ Occurrence is the likelihood of the failure happening based on past experience ✓ Detection is based on the monitoring systems in place and on how likely a failure can be detected

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By asking a series of questions, each main part of the cleanroom or isolator system can be grouped or classified into key parts. Such questions include: ✓ What is the function of the equipment? What are its performance requirements? ✓ How can it fail to fulfil these functions? ✓ What can cause each failure? ✓ What happens when each failure occurs? ✓ How much does each failure matter? What are its consequences? ✓ What can be done to predict or prevent each failure? ✓ What should be done if a suitable proactive task cannot be found? The scoring is 1 (very good) to 5 (very bad). Therefore, a likelihood of high severity would be rated 5; high occurrence rated 5; but a good detection system would be rated 1. Using these criteria, a final FMEA score is produced from:  Severity score x Occurrence score x Detection score  Decisions on further action will depend upon the score produced. There is no published guidance on what the score that dictates some form of action should be. However, 27 is the suggested score for the cut-off value at which action is required. This is based on 27 being the score derived when the mid-score is applied to all three categories (i.e., the numerical value '3' for severity 3 x occurrence 3 x detection 3) and the supposition that if the mid-rating (or a higher number) is scored for all three categories, then at a minimum, the system should be examined in greater detail.

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Figure 4  Isolator Operation Example

 An example of one area of an isolator operation, and the risks associated with the room in which the isolator is housed, is examined below.

Description of the Critical Area: The isolator is situated in an unclassified room. There is no requirement to place a sterility testing isolator in a classified room. FMEA Schematic:

Process Step

Failure Mode

Loading isolators pre-sanitisation, performing sterility testing

That contamination from the room could enter transfer or main isolators

Measures to Detect Failure Would be shown from reduced evaporation rate for isolator sanitisation, poor environmental monitoring results in main isolator, potential sterility test failures. Sanitisation cycle has been validated using biological indicators of 106 spores.

Significance of Failure Reduced efficiency of transfer isolator sanitisation, contamination inside main isolator

Occurrence (score)

Detection Systems

1

Isolator room is monitored monthly for viables and particles, staff wear over-shoes on entry, Dycem mat in place, entry to room has controlled access, environmental monitoring performed inside main isolator. Isolators are at positive pressure to the room, and air is HEPA filtered.

Severity of Consequence (score) 3

Detection (score) 1

FMEA score: 3 x 1 x 1 = 3 Analysis: There is no problem to be considered from the room environment described. Entry to the room is controlled; the sanitisation cycle has been challenged with a level of micro-organisms far greater than would ever be found in the environment (spores of Geobacillus stearothermophilus); all items entering the isolator are sanitised (using a chlorine dioxide-based sporicidal disinfectant); and the isolator itself is an effective, positive pressure barrier to the outside (at >15 pascals).  As detailed earlier, environmental monitoring is performed inside the isolator during testing. This monitoring, which has an action level of 1 CFU (Colony Forming Unit), is designed to detect any potential contamination inside the isolator environment. 14

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NUMERICAL APPROACHES A third component of the risk assessment approach is to evaluate a risk once an activity has taken place. Then, by using a largely numericallydriven set of tools, repeatability and reproducibility can be ensured. Examples of individual out-of-limits results and data-sets relating to an operation are examined below using examples from an aseptic filling process. Following this, an example of an overall assessment of different processes over time is explored. Numerical approaches are useful in applying a level of consistency between one decision and another. Individual Assessments  The section below details some methods that can be used to quantify the risk of contamination in pharmaceutical cleanrooms. The models outlined are based on the work performed by Whyte and Eaton (2003a and b). ➤

Estimating the Risk to Product Using Settle Plate Counts  The method applies to the assessment of settle plates at the pointof-fill, under the Grade A zone. It allows an estimate of the probable contamination rate to the product as derived from the following equation:

Contamination rate (%)

=

Settle plate count

x

Area of product

x

Area of petri dish Time product exposed

x 100

Time settle plates exposed

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The fixed value is the area of the petri dish, which for a 90mm plate, is 64 cm2. ➤

Settle Plate Count Worked Example:

Area of petri dish = 64 cm2 = 1 cfu ✓ Settle plate count ✓ Neck area of product = 1 cm 2 = 1 minute ✓ Exposure time of product ✓ Exposure time of settle plate = 240 minutes By inserting these example values into the equation: ✓

1 x 1 x 1 64

= 0.000065 x 100 =

0.0065%

240

The formula can also be applied to the monitoring of product filtration activities when ‘1’ is entered as a constant for neck area of product. There is no available guide as to what percentage constitutes which level of risk. The 0.03% figure has been used by some practitioners. This is based on the Parenteral Drug Association Survey of Aseptic Filling Practices (2002), where it is common in the pharmaceutical industry to allow 0.03% of broth bottles in a media simulation trial to exhibit growth at a ‘warning level’ (where 0.03% = 1/3,000, with 3,000 being the average size of a media fill). An ‘action level’ is often set as 3/3,000 bottles or 0.1%. This would constitute a high risk. Logically, the range between 0.03 and 0.1 would be a medium risk (Whyte and Eaton, 2004c). Therefore, where the ‘risk’ is that of micro-organisms detected on a settle plate, with a probability of